RECOMBINATE 1000 IU

Baxter S.A.

SUMMARYOF PRODUCT CHARACTERISTICS

" עעבקנהזןולעטמרופ " רשואוקדבנונכותותואירבהדרשמי ." רשואמןולע " ץרמ 2011 .

“This leaflet format has beendeterminedbythe Ministryof Health and the content thereof has been checked

and approved.” Date ofapproval: March 2011.

CLEAN COPY

1. NAMEOF THE MEDICINAL PRODUCT

Recombinate, 250 IU/10ml, powderandsolvent forsolution for injection.

Recombinate, 500 IU/10ml, powderandsolvent forsolution for injection.

Recombinate, 1000 IU/10ml, powderandsolventfor solution for injection.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Recombinate 250 IU is presentedasa lyophilisedpowder for solution for injection,containing nominally

250 IUoctocog alfa, recombinantcoagulationfactorVIII per vial.

The product containsapproximately25 IU/mloctocog alfa, recombinant coagulation factorVIII when

reconstituted with10mlof sterile water forinjections.

Recombinate 500 IU is presentedasa lyophilisedpowder for solution for injection,containing nominally

500 IUoctocog alfa, recombinantcoagulationfactorVIII per vial.

The product containsapproximately50 IU/mloctocog alfa, recombinant coagulation factorVIII when

reconstituted with10mlof sterile water forinjections.

Recombinate1000 IUis presentedasa lyophilisedpowder for solution for injection,containing nominally

1000 IUoctocog alfa, recombinantcoagulationfactorVIII per vial.

The productcontainsapproximately100 IU/mloctocog alfa,recombinant coagulation factorVIII when

reconstituted with10mlof sterile water forinjections.

The potencyis determinedusing theEuropean Pharmacopoeia chromogenic assayagainst the FDA Mega

Standardcalibrated to the WHO Standard. Thespecific activityofRecombinateis approximately4000 – 8000

IU/mg protein.

RecombinatecontainsrecombinantcoagulationfactorVIII(INN:octocogalfa).Octocogalfa(recombinant

coagulationfactor VIII) is apurifiedproteinconsistingof 2332 amino acids.It has an aminoacid sequencethat

iscomparableto factorVIII,andpost-translationalmodificationsthat are similar tothoseofthe plasmaderived

molecule. Recombinant coagulation factor VIII isa glycoprotein that is expressed by geneticallyengineered

mammaliancellsderivedfromaChinesehamster ovarycellline.

Forexcipients, seesection 6.1.

3. PHARMACEUTICAL FORM

Powder and solvent for solutionforinjection.

White to off-white friablepowder. Thesolvent (sterilisedwater for injections) isaclear andcolorless liquid.

4. CLINICAL PARTICULARS

4.1.Therapeutic indications

The use of Recombinate is indicatedin the treatmentand prophylaxis of bleedingin patientswith haemophilia

A (congenitalfactorVIIIdeficiency). Recombinate isalsoindicated in theperioperativemanagement of

patientswith haemophilia A.

Recombinateis appropriatefor use in children ofallages, includingthe newborn.(Safetyand efficacystudies

have been performedin both previouslytreated andpreviouslyuntreated children.)

Baxter S.A.

SUMMARYOF PRODUCT CHARACTERISTICS

The product does notcontain von Willebrand factor and istherefore isNOT indicated for the treatment of von

Willebrand’s disease.

4.2.Posologyand method of administration

Posology

The dosageand duration ofthesubstitution therapydepend ontheseverityof the disorder ofthe haemostatic

function, on the locationand extent ofbleedingepisodes, andontheclinicalconditionofthe patient.The

treatmentshould be carriedout in collaboration witha physicianwith experiencein bleeding disordersanda

laboratorywiththecapacitytomeasure plasmaAHFconcentration.

The numberof units of factor VIIIadministered isexpressed in International Units (IU),which are related to

the current WHO standard for factor VIII products. Factor VIIIactivityinplasma is expressed eitheras a

percentage (relative to normal human plasma) or in International Units (relative to an International Standard

of factor VIII inplasma). One International Unit (IU) offactor VIII activityisequivalent tothat quantityof

factor VIII in one ml of normal human plasma.

The expectedin vivopeak in Recombinate levelexpressedas IU/dl of plasma or%(percent) ofnormalcanbe

calculated bymultiplying the doseadministered per kgbodyweight(IU/kg) bytwo.

The calculation methodis illustrated inthefollowing examples :

# unitsadministeredx2%/IU/kg

Expected factor VIIIincrease, %= -----------------------------------------

bodyweight (kg)

1750IU x 2%/IU/kg

Example fora 70 kg adult: --------------------------=~50 %

70 kg

or

bodyweight(kg) x desiredfactor VIII increase,%

Dosagerequired (IU)= --------------------------------------------------------------

2 %/IU/kg

40 kg x70%

Example fora40kgchild: ----------------- = 1400IU

2 %/IU/kg

The carefulcontrolof the substitutiontherapyisespeciallyimportant incases ofmajorsurgeryor life

threatening haemorrhages. Although dosage can beestimated bythe calculationabove, it is strongly

recommendedthat whenever possible,appropriatelaboratorytests including serial AHFassaysbe performed

on the patient’s plasma atsuitable intervals to assurethatadequate AHF levelshavebeen reached and are

maintained.If the patient’s plasma AHF failsto reachexpected levelsor ifbleeding is not controlledafter

adequate dosage, the presence of inhibitors should besuspected. Byperforming appropriate laboratorytests, the

presence of an inhibitor can be demonstrated and quantified in termsof AHF International Unitsneutralisedby

eachml of plasma(Bethesda Units) or bythe total estimated plasma volume. If the inhibitor ispresent at levels

less than 10BethesdaUnits perml,administration ofadditional AHFmayneutralise theinhibitor. Thereafter,

theadministrationofadditional AHF InternationalUnits shouldelicit thepredicted response. Thecontrol of

AHF levelsby laboratory testsisnecessary in thissituation.Inhibitor titersabove10 BethesdaUnitsperml

may makehaemostasiscontrolwithAHF eitherimpossibleor impracticalbecauseof the verylargedose

required.

Recombinateisappropriatefor the use inchildrenofall ages, including the newborn (safetyand efficacy

studies havebeenperformedin bothpreviouslytreatedand previouslyuntreated children; see section5.1).

Baxter S.A.

SUMMARYOF PRODUCT CHARACTERISTICS

Thefollowingdosage schedule providedin tableImaybeusedasaguideforadultsandchildren. Theamount

to beadministeredand thefrequencyof applicationshould alwaysbe oriented totheclinicaleffectivenessin

the individualcase.

Recombinate mayalsobeadministeredfor prophylaxis(short orlong term) of bleeding, asdeterminedbythe

physician onan individualbasis.

TableI:Dosageschedule

HAEMORRHAGE

Degreeof haemorrhage Requiredpeak

postinfusionAHFactivity

in the blood † (as %of

normal orIU/dLplasma) *

Frequency of infusion

Earlyhaemarthrosisor muscle

bleed or oralbleed 20 – 40 Begininfusion every12to24 hours for

one tothree daysuntilthe bleeding

episodeasindicatedbypainisresolved

orhealing is achieved.

Moreextensivehaemarthrosis,

muscle bleed,or haematoma 30 – 60 Repeatinfusionevery12to24 hoursfor

usuallythree daysormore untilpain and

disabilityare resolved.

Lifethreatening bleedssuchas

headinjury, throat bleed,severe

abdominal pain 60 – 100 Repeatinfusionevery8to24 hours until

threatisresolved.

SURGERY

Type of operation Frequency of infusion

Minorsurgery,including tooth

extraction 30 – 60 Asingleinfusion plusoralantifibrinolytic

therapywithinone hourissufficientin

approximately70 % ofcases.Every24

hours, atleast1 day,until healingis

achieved.

Majorsurgery 80 – 100

(pre- andpostoperative) Repeat infusion every8 to 24hours

depending on stateofhealing.

† This representspeak AHF activity for patients with theexpectedmean half-life for factor VIII. If considered necessary,

peak activityshould be measured withinone-half hour after administration. For patients with relativelyshorthalf-lifes

for factor VIII itmay be necessaryto increase the dosage and/or frequency of administration.

Each vialof Recombinate is labelled withthe (recombinant) antihaemophilic factor, Recombinateactivityexpressedin

IU pervial. Thispotencyassignmentisreferenced to the World Health Organisation InternationalStandard for factor

VIII:C concentrate. Experiments have shown that,to achieve accurateactivity levels,such a potency assay shouldbe

conducted using plastictesttubes and pipetsas well assubstrate containing normallevels of vonWillebrand factor.

Forlongterm prophylaxis againstbleeding in patientswithsevere haemophiliaA,the usualdosesare20to

40IU of factorVIII per kgbodyweightat intervals of2 to3days.Insomecases,especiallyinyounger patients,

shorterdosageintervalsorhigherdosesmay benecessary.

Baxter S.A.

SUMMARYOF PRODUCT CHARACTERISTICS

PatientsshouldbemonitoredforthedevelopmentoffactorVIIIinhibitors.IftheexpectedfactorVIIIactivity

plasmalevelsarenot attained,orifbleeding isnot controlledwithanappropriatedose, anassayshould be

performed to determineifafactorVIIIinhibitorispresent.In patientswithhighlevels of inhibitor,factorVIII

therapymaynot beeffectiveand other therapeutic options should beconsidered.Managementof such patients

should bedirectedbyphysicianswithexperience in the careofpatients withhaemophilia.

See also4.4.

Method of administration

The preparation isto beadministered intravenouslyafter reconstitution with the providedsolvent (see section

6.6). It is recommended that administration commence within threehours after reconstitution.The reconstituted

materialshould not be refrigerated.The preparation canbe administeredat a rate of up to 10mlperminute.

The pulse rate should bedetermined beforeand during administration of Recombinate. Should a significant

increaseoccur, reducingtherateofadministrationortemporarilyinterruptingthe injection usuallyallows the

symptoms todisappear promptly(seesections4.4., and 4.8).

4.3. Contraindications

Hypersensitivityto theactivesubstanceor toanyoftheexcipients. Knownallergicreactionto bovine,mouse

or hamster protein.

4.4.Special warningsandprecautionsforuse

Severeallergic reactionstoRecombinate havebeenreported. Patientswithknownhypersensitivityto bovine,

mouseorhamsterproteinsshouldbetreatedwithcaution.Patientsshouldbeinformedoftheearlysignsof

hypersensitivityreactionsincludinghives, generalised urticaria, tightness of the chest, wheezing,

hypotensionandanaphylaxis.If allergic or anaphylactic reactionsoccur, the injection/infusion shouldbe

stopped immediately. Facilities for theappropriate treatment of shockshould beavailable.

IfplasmaAHFlevelsfailtoreachexpectedlevels orif bleedingis notcontrolled afteradequate dosage,

appropriate laboratoryteststo detect thepresence of inhibitorshouldbe performed.

The formation of neutralising antibodies (inhibitors) to FactorVIII isa known complication in the

management of individuals with haemophilia A. These inhibitors are usuallyIgG immunoglobulinsdirected

against FactorVIII procoagulant activity, which are quantified in BethesdaUnits (BU) permlof plasma

using themodified Bethesda assay. The risk of developing inhibitors iscorrelatedto the extent of exposure

to Factor VIII, the riskbeing highest within the first 20 exposure days, and to other genetic and

environmental factors. Rarely, inhibitorsmaydevelop after the first 100 exposure days. Cases of recurrence

of inhibitors (low titre) have been observed after switching fromone recombinant factor VIII product to

another in previouslytreated patients with more than 100 exposure dayswho have a historyof inhibitor

development.

Patients treated with recombinant coagulation factorVIII shouldbe carefullymonitored for the development

of inhibitorsbyappropriate clinical observations and laboratorytests. See also section 4.8.

In the interest of patients, it is recommended that,whenever possible, everytime thatRecombinateis

administeredto them, the nameand batchnumber of the product shouldbe registered.

This medicinal product contains 1.5 mmol sodiumper dose. Tobe taken intoconsideration bypatients ona

controlled sodiumdiet.

4.5.Interactionwith other medicinal products and other forms of interaction

No interactionswith othermedicinal products havebeen observed.

Baxter S.A.

SUMMARYOF PRODUCT CHARACTERISTICS

4.6.Pregnancy and lactation

Animal reproductionstudies havenotbeenconductedwith factorVlll. Basedonthe rare occurrenceof

haemophilia A in women,experience regarding the useof factorVIII during pregnancyand breast-feedingis

not available.Therefore, factorVIIIshould be usedduring pregnancyand lactationonlyif clearlyindicated.

4.7.Effects on ability to driveand use machines

Noeffects onabilityto driveand usemachineshavebeen observed.

4.8.Undesirable effects

The following table lists the adverse reactions observed fromspontaneous reportingand inclinical trials.

Within each frequencygrouping, undesirable effectsare presentedin order ofdecreasing seriousness.

Frequency has been evaluated usingthefollowing criteria: very common ( 1/10), common (1/100, <1/10),

uncommon ( 1/1 000, <1/100), rare (1/10 000, <1/1 000), veryrare (<1/10 000) and not known (cannot be

estimated fromtheavailable data).

MedDRASystemOrgan Class Frequency MedDRAPreferred Term

Infections and infestationsuncommon Ear infection

Blood andlymphatic systemdisorders common Factor VIII inhibition 1

Immune systemdisorders not known

Anaphylactic shock

Hypersensitivity 2

Nervous systemdisorders uncommon Dizziness

Tremor

not known Syncope

Headache

Cardiac disorders not known Cyanosis

Tachycardia

Vascular disorders

uncommonEpistaxis

Flushing

Haematoma

Hypotension

Pallor

Peripheral coldness

Respiratory,thoracic and mediastinal

disorders uncommonPharyngolaryngeal pain

not known Dyspnea

Cough

Chest discomfort

Wheezing

Gastrointestinal disorders uncommon Nausea

not known Vomiting

Abdominal discomfort

Baxter S.A.

SUMMARYOF PRODUCT CHARACTERISTICS

Skin and subcutaneous tissue disorders uncommon Hyperhydrosis

Pruritus

Rash

Rash maculo-papular

not known Urticaria

Skin exfoliation

Musculoskeletal and connective tissue

disorders uncommon Pain in extremity

General disorders and administration site

conditions commonChills

uncommon Fatigue

Pyrexia

Investigationsuncommon Acoustic stimulation tests

abnormal

In the PTPclinical trial (PTP = previouslytreatedpatients), none of the 71subjects developedde novo

FVIII antibody, but 22 of 72 evaluable per protocol PUPs(PUP=previouslyuntreated patients) treated with

Recombinate did develop FVIII antibodies and theabovefrequencywas based on the PUP data. Of the22,

10 were hightitre ( 5 Bethesda Units) and 12 were low titre (< 5 Bethesda Units).

2 Earlysignsof hypersensitivityreactions aree.g. urticaria, dyspnea, cough, chest discomfort, wheezing,

anaphylaxis, rash, hypotension, pruritus,chills, flushing, pyrexia,cyanosis, tachycardia, vomiting, syncope,

headache. Caution is advised in patients with knownallergic reactions to constituents of the preparation (See

sections 4.3 and 4.4).

Theformation of neutralising antibodies(inhibitors) tofactorVIII isa known complicationinthemanagement

of individuals with haemophiliaA. These inhibitorsare invariablyIgG immunoglobulins directed against the

factor VIII procoagulantactivity, whichareexpressedasBethesdaUnits (BU) perml of plasma.

The risk of developing inhibitors iscorrelated to the exposure to antihaemophilic factorVIII, this risk being

highest withinthe first 20exposure days. The reportedincidence of inhibitoryantibodiesin patients with severe

haemophiliaAwho are at high risk forinhibitor development (i.e.PUPs:previouslyuntreatedpatients)is

estimated in studies to be31% for Recombinate,which is within the reported range for plasma derived AHF.

Patientstreated with Recombinate should be carefullymonitored for the development of inhibitoryantibodies

byclinical observationsand laboratorytests.

4.9. Overdose

Nosymptoms of overdoseare known.

5. PHARMACOLOGICALPROPERTIES

5.1.Pharmacodynamic properties

Pharmacotherapeutic Group:antihemorrhagics: blood coagulation factor VIII. ATC code: B02BD02.

The factorVIII/von Willebrand factorcomplex consists of twomolecules (factor VIIIand von Willebrand

factor) with different physiological functions.

When infused into ahaemophiliac patient, factor VIII binds tovon Willebrand factor in the patient’s

circulation..

Baxter S.A.

SUMMARYOF PRODUCT CHARACTERISTICS

Activated factor VIII actsas a cofactor for activatedfactor IX, accelerating the conversion of factor X to

activated factor X. Activated factor X converts prothrombininto thrombin. Thrombinthen converts

fibrinogen intofibrin and a clot can beformed. Haemophilia A is a sex-linked hereditarydisorder of blood

coagulationdue todecreased levels of factor VIII:C and results in profuse bleeding into joints, muscles or

internal organs, either spontaneouslyor as a result ofaccidental or surgical trauma. Byreplacement therapy

the plasmalevels of factor VIII areincreased, therebyenabling a temporarycorrection of the factor

deficiencyand correction of the bleeding tendencies.

Recombinate has been studied in 71previouslyuntreated children (PUP’s). Median age of the cohort atthe

time of firstRecombinate infusion was 10months(range: 2 daysto 50 months. The product waswell

tolerated and not associatedwith significant short-term adverseeffects. Its clinical efficacywas comparable

to other full-length FVIIImolecules inboth the treatmentofacute haemorrhage and for surgical prophylaxis

(10 subjects had undergonesurgical interventions). Long-termfollow-up of the cohort revealed an incidence

of product-related adverseevents of 0.86/1000 infusions, none serious or life-threatening.

5.2.Pharmacokinetic properties

Pharmacokinetic studieson 69 previouslytreatedpatients revealed the circulatingmean half-life for

Recombinateto be 14.6 ±4.9 hours (n= 67), whichwasnot statisticallysignificantlydifferent fromHemofil

M, the plasma-derivedantihaemophilic factor (human)(pdAHF). Themean half-life ofHemofil M was 14.7±

5.1 hours (n= 61). The actual baselinerecoveryobservedwithRecombinateafter infusionofa 50IU/kg dose

was 123.9±47.7 IU/dl (n= 23), whichissignificantlyhigher than the actual HemofilM baselinerecoveryof

101.7 ±31.6IU/dl (n = 61). However, the calculated ratio ofactual toexpected recovery(i.e. 2 %increment in

factor VIII activityper IUrAHF/kg bodyweight) with Recombinate(121.2±48.9 %) issimilar to thatof

HemofilM (123.4 ±16.4%).

A total of 494 recoverystudies were obtained from 68previouslyuntreatedpatients. Two hundred and twelve

recoverystudieswere performed when thepatientswerebeingtreatedfor bleeds withamean± SDactual

recoveryof 70.0 ± 37.9 IU/dl (n = 208) (four recoveriesomitted fromanalysis as outliers). The high variability

is due to thewiderange ofactual dose given, 13.8 to103.2 IU/kg(mean±SD of36.0 ±16.2and amedianof

30.2 IU/kg).Toaccount for these variable dosinglevels,the actual/predictedrecoveryratioswere calculated,

resulting inamean of1.0± 0.3.

A total of68recoverystudies wereperformed whenthe patientswerereceiving a follow-up infusion for

continuedtreatment ofa pre-existing bleed. TheactualfactorVIIIrecoverylevelwascorrectedforthe pre-

infusionfactorVIIIlevel. The mean ± SD actual recoverywas 88.6 ±38.2 IU/dl (n = 66)(two recoveries

omitted fromthe analysisasoutliers).Again, the widerange ofactual doses given,18.5 to 85.7 IU/kg (mean±

SD of 38.6±15.9 and amedian of 32.1 IU/kg), results insubstantial variation inthe recoverylevelsobserved.

The mean±SDactual/predictedrecoveryratio was 1.0±0.3withamedian of 1.0.

A total of 214 recoverystudies wereperformedwhenpatientswere instablestate resulting inamean actual

recoveryof 71.6 ±29.7IU/dl (n= 209)(fiverecoveriesomitted fromtheanalysis as outliers).The doses given

ranged from10.4 to 68.1 IU/kg(mean±SD of 38.0±12.7 anda medianof 36.1IU/kg). The mean ±SD

actual/predicted recoveryratiowas 1.0± 0.3.

5.3.Preclinical safety data

Recombinate actslike the endogenousfactor VIII.Dosesseveral times therecommended human dosage per

kilogrambodyweight showno toxic effects on laboratoryanimals. Recombinate was tested formutagenicityat

dosesconsiderablyexceeding plasmaconcentrationsof AHFin vitroandat doses upto ten times theexpected

maximum clinicaldoseinvivo, anddid notcausereverse mutations, chromosomalaberrations,oran increase in

micronuclei in bonemarrow polychromatic erythrocytes.Sinceclinical experience providesno evidence for

tumorigenic and mutagenic effects,long-termstudiesin animalstoevaluatecarcinogenicpotential are not

consideredimperative.

Baxter S.A.

SUMMARYOF PRODUCT CHARACTERISTICS

6. PHARMACEUTICAL PARTICULARS

6.1.List of excipients

Powder:

human albumin solution;

sodiumchloride;

histidine;

macrogol 3350;

calcium chloride dihydrate.

Solvent:

water for injections.

6.2.Incompatibilities

In the absence ofcompatibilitystudies,thismedicinal productshould not bemixed with othermedicinal

products orsolvents.

Onlytheprovidedinfusionsetsshould be usedbecause treatment failurecanoccur as aconsequenceofhuman

coagulation factor VIII adsorption to theinternalsurfacesof some infusion equipment.

6.3.Shelf life after reconstitution

Afterreconstitution, Recombinate should be administeredwithinthree hours

6.4.Special precautions for storage

Store ina refrigerator (2°C– 8°C).

Do notfreeze.

Store in the outer carton inorder to protectfrom light.

Withinits shelf-life, the productmaybestoredat 15°C- 25°C prior to use for up to sixmonths.

Donot return torefrigerationfollowingstorageat 15°C - 25°C.

Forstorage conditions of the reconstituted medicinal product,see section6.3.

6.5.Nature and contents of container

A single pack contains apowder vial,a 10 ml solvent vial (both type I glass with rubber stoppers) anda

device for reconstitution (BAXJECT II) + one sterile single-use plastic syringe + one sterile mini-infusions

set + 2 alcohol swabs + 2 plasters.

Alternativelyto BAXJECT II a needle device for reconstitution comprising one sterile double-ended needle

(to transfer the solvent into the Recombinate vial),one sterilefilter needle(to transfer the reconstituted

solution into the syringe) can be provided.

Pack size of 1

6.6.Special precautions for disposal andother handling

The preparation is to be administered intravenouslyafter reconstitutionwith the provided sterilewater for

injections.The disposable plasticsyringeprovidedwiththe product should be used.

- Use within three hours after reconstitution.

- Do not refrigerate preparation after reconstitution.

- Anyunusedproduct or wastematerial shouldbe disposed of in accordance with local

requirements.

Baxter S.A.

SUMMARYOF PRODUCT CHARACTERISTICS

- The solutionshouldbe clear or slightlyopalescent.Do notuse solutions thatare cloudyorhave

deposits. Reconstituted productsshould be inspected visuallyfor particulatematter and

discolorationprior to administration.

- Do notuse ifthe product, its sterile barrier systemor its packagingis damaged or shows anysignof

deterioration.

Baxter S.A.

SUMMARYOF PRODUCT CHARACTERISTICS

Reconstitution: Use Aseptic Technique

Reconstitution with BAXJECT II Reconstitution with needles

1. Bring Recombinate (powder)and SterilisedWaterfor

Injections(solvent) to15-25°C. 1.Bring Recombinate (powder)and SterilisedWater

for Injections (solvent)to15-25°C.

2. Remove capsfrompowder and solventvials. 2.Remove capsfrompowder and solventvials.

3. Cleanse stopperswith alcohol swabs. Place thevials on

a flat surface. 3.Cleanse stopperswith alcohol swabs. Place thevials

onaflat surface.

4.Open the package of BAXJECT II device by peeling

away the paper lidwithout touchingthe inside (Fig. a).

Donotremove thedevicefromthe package. 4.Removeprotecting coveringfromoneendofdouble-

endedneedleandinsertexposedneedlethrough

stopperofsolventvial.

5. Turn thepackageover and insert the clearplastic spike

throughthe solventstopper.Gripthe package at its

edgeand pullthe package off BAXJECT II (Fig. b). Do

notremove thebluecapfromBAXJECT II device. 5.Removeprotective coveringfromotherendof

double-endedneedle.Invertsolventvialover the

upright Recombinatevial, thenrapidlyinsertfreeend

oftheneedlethrough the Recombinate vialstopperat

its center.Thevacuuminthevial will draw inthe

solvent.

6.With BAXJECT II attachedtothe solventvial, invert

the systemso that thesolventvial is ontop ofthe

device. Insertthewhiteplastic spike throughthe

Recombinate stopper. Thevacuumwill draw the solvent

into theRecombinatevial (Fig. c). 6.Disconnectthetwovialsbyremovingneedlefrom

solventvialstopper,thenremoveneedlefrom

Recombinate vial. Swirlgently until all material is

dissolved. Be sure that Recombinate is completely

dissolved,otherwise active material will beremoved

bythe filter needle.

7. Swirlgently until allmaterialis dissolved.Be sure that

Recombinate is completely dissolved;otherwise active

material will notpass through thedevice filter. The

productdissolves rapidly(usuallyinless than1 minute).

Fig.a Fig. b Fig.c

Administration: Use Aseptic Technique

It is recommended that administrationcommencewithin

threehours after reconstitution.The reconstituted

materialshouldnotberefrigerated. Parenteraldrug

productsshouldbeinspectedfor particulate matterand

discolorationpriortoadministration,wheneversolution

and containerpermit. A colourless tofaintly yellow

appearance is acceptablefor Recombinate. Itisrecommendedthatadministration commence

withinthree hours after reconstitution.The

reconstituted materialshouldnotberefrigerated.

Parenteral drugproducts shouldbeinspectedfor

particulate matter anddiscolorationprior to

administration,wheneversolution andcontainer

permit. A colourless tofaintly yellow appearance is

acceptable for Recombinate.

1. Remove theblue capfromBAXJECT II.DONOT

DRAW AIR INTOTHE SYRINGE.Connectthe

syringeto BAXJECTII(Fig.d). 1.Attachfilter needle tothedisposable syringeand

drawbackplunger toadmitair intosyringe.

2. Invert the system(with concentratevial on top). Draw

the concentrate intothe syringe bypullingthe plunger

back slowly (Fig. e). 2.Insert filterneedle into reconstitutedRecombinate.

3. Disconnect thesyringe. 3.Injectair into vial andthenwithdraw the

reconstitutedmaterial intothe syringe.

Baxter S.A.

SUMMARYOF PRODUCT CHARACTERISTICS

4. Attachthe administrationset tothe syringe. Inject

intravenously.Thepreparation canbe administered ata

rateofupto10mlper minute.Thepulserateshouldbe

determinedbeforeand duringadministration of

Recombinate. Should asignificant increaseoccur,

reducingthe rateofadministrationortemporarily

interrupting the injection usually allows thesymptoms

todisappearpromptly. (See sections4.4 and4.8). 4.Removeand discard filterneedle.Attach

administrationset tothe syringe.Inject

intravenously. The preparationcan beadministeredat

a rateofupto10mlper minute. Thepulserate

shouldbe determinedbefore andduring

administration ofRecombinate. Should a significant

increaseoccur, reducing therate of administration or

temporarily interruptingthe injectionusually allows

the symptoms todisappear promptly. (See sections

4.4and 4.8).

Fig. dFig. e

5.A separateunusedfilter needlemust beused to

withdraw eachvial of reconstitutedRecombinate.

7. REGISTRATION NUMBERS

Recombinate, 250 IU/10ml, powderandsolvent forsolution for injection : 143 82 31871 00.

Recombinate, 500 IU/10ml, powderandsolvent forsolution for injection : 143 83 31872 00.

Recombinate, 1000 IU/10ml, powderand solventfor solution for injection: 143 84 31873 00.

8. MANUFACTURER

BaxterS.A., Lessines, Belgium

9 LICENCE HOLDER

TevaMedical Marketing Ltd.,

Haorgim St. 2,Ashdod 77100.

EUAPPROVALDATE: 3 March 2009.

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